Healing or self-damage: Immunoreceptors' 'split personality'

A mast cell with IgE antibodies bound to the Fc receptors on its surface
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LOS ALAMOS, N.M., April 2003 -- Sometimes described as a "liquid brain," the immune system is continually poised at the edge of disaster, required to aggressively attack invading pathogens without damaging its own body. The challenge of understanding the complexity of signaling entailed in such a delicately balanced system has been taken up by Los Alamos National Laboratory researchers, who are developing a mathematical model of immunoreceptors, a large and diverse group of proteins that decode regulatory signals.

As recently reported in Molecular Immunology, a team led by Byron Goldstein, and including Michael Blinov, Jim Faeder, Bill Hlavacek, Antonio Redondo, and Carla Wofsy, is studying the Fc epsilon receptor.

This receptor is a mast-cell membrane protein that normally functions in inflammation to help remove pathogenic organisms but which, when regulation goes awry, serves as a signaling intermediary in allergic reactions.

The receptor binds the IgE class of antibodies and is activated when foreign substances (antigens) bind to those antibodies. Receptor activation initiates a cascade of biochemical changes that culminates in the secretion of histamine and other inflammatory biochemicals. In allergic reactions, the inflammatory process becomes excessive, leading to discomfort (as in hay fever) or even to death by asphyxiation (as in extreme insect-sting reactions).

By creating and studying a mathematical model of this signaling cascade, the investigators hope to understand the behavior of the signaling system as a whole. In the process, they should also be able to glean more insight into the complex subcellular networks that regulate this form of receptor-mediated signaling. As emphasized by Faeder, "Signaling has been thought of as a linear chain of events, but it's not like that at all."

The investigators hope to expand the model to include additional components of the signaling cascade. Another goal is to find reduced models that encompass only the key biochemical interactions in this cascade to make it easier for experimentalists to identify critical points for potential drug treatments. Currently available drugs like antihistamines and ibuprofen tend to intervene after the fact, that is, after this signaling cascade has run its course, and therefore relieve symptoms rather than address causes.

"A detailed mathematical model of a signaling cascade for an immune system receptor has never been done before," adds Goldstein.

"What's amazing is that as complicated as the system is, our model works. It's consistent with a wide array of experimental observations." This, of course, is potentially good news for allergy sufferers, since researchers may some day be able to use the findings of this model to design more efficacious medications that intervene in the allergic process at an earlier stage.

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Los Alamos National Laboratory is operated by the University of California for the National Nuclear Security Administration (NNSA) of the U.S. Department of Energy and works in partnership with NNSA's Sandia and Lawrence Livermore national laboratories to support NNSA in its mission.

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